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Tumor Biology |
Immunology and Oncology Unit, Department of Surgical Sciences, David Maddison Clinical Sciences Building, Newcastle, NSW 2300, Australia
Past studies have shown that apoptosis mediated by TNF-related apoptosis-inducing ligand (TRAIL) is regulated by the expression of two death receptors [TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2] and two decoy receptors (TRAIL-R3 and TRAIL-R4) that inhibit apoptosis. In previous studies, we have shown that TRAIL but not other members of the tumor necrosis factor family induce apoptosis in approximately two-thirds of melanoma cell lines. Here, we examined whether the expression of TRAIL-R at the mRNA and protein level in a panel of 28 melanoma cell lines and melanocytes correlated with their sensitivity to TRAIL-induced apoptosis. We report that at least three factors appear to underlie the variability in TRAIL-induced apoptosis. (a) Four of nine cell lines that were insensitive to TRAIL-induced apoptosis failed to express death receptors, and in two instances, lines were devoid of all TRAIL-Rs. Southern analysis suggested this was due to loss of the genes for the death receptors. (b) Despite the presence of mRNA for the TRAIL-R, some of the lines failed to express TRAIL-R protein on their surface. This was evident for TRAIL-R1 and more so for the TRAIL decoy receptors TRAIL-R3 and -R4. Studies on permeabilized cells revealed that the receptors were located within the cytoplasm and redistribution from the cytoplasm may represent a posttranslational control mechanism. (c) Surface expression of TRAIL-R1 and -R2 (but not TRAIL-R3 and -R4) showed an overall correlation with TRAIL-induced apoptosis. However, certain melanoma cell lines and clones were relatively resistant to TRAIL-induced apoptosis despite the absence of decoy receptors and moderate levels of TRAIL-R1 and -R2 expression. This may indicate the presence of inhibitors within the cells, but resistance to apoptosis could not be correlated with expression of the caspase inhibitor FLICE-inhibitory protein. mRNA for another TRAIL receptor, osteoprotegerin, was expressed in 22 of the melanoma lines but not on melanocytes. Its role in induction of apoptosis remains to be studied. These results appear to have important implications for future clinical studies on TRAIL.
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J. J. Lum, A. A. Pilon, J. Sanchez-Dardon, B. N. Phenix, J. E. Kim, J. Mihowich, K. Jamison, N. Hawley-Foss, D. H. Lynch, and A. D. Badley Induction of Cell Death in Human Immunodeficiency Virus-Infected Macrophages and Resting Memory CD4 T Cells by TRAIL/Apo2L J. Virol., November 15, 2001; 75(22): 11128 - 11136. [Abstract] [Full Text] [PDF]
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C. S. Mitsiades, S. P. Treon, N. Mitsiades, Y. Shima, P. Richardson, R. Schlossman, T. Hideshima, and K. C. Anderson TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications Blood, August 1, 2001; 98(3): 795 - 804. [Abstract] [Full Text] [PDF]
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M. Cuello, S. A. Ettenberg, A. S. Clark, M. M. Keane, R. H. Posner, M. M. Nau, P. A. Dennis, and S. Lipkowitz Down-Regulation of the erbB-2 Receptor by Trastuzumab (Herceptin) Enhances Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Apoptosis in Breast and Ovarian Cancer Cell Lines that Overexpress erbB-2 Cancer Res., June 1, 2001; 61(12): 4892 - 4900. [Abstract] [Full Text] [PDF]
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A. V. Franco, X. D. Zhang, E. Van Berkel, J. E. Sanders, X. Y. Zhang, W. D. Thomas, T. Nguyen, and P. Hersey The Role of NF-{{kappa}}B in TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis of Melanoma Cells J. Immunol., May 1, 2001; 166(9): 5337 - 5345. [Abstract] [Full Text] [PDF]
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R. Di Pietro, P. Secchiero, R. Rana, D. Gibellini, G. Visani, K. Bemis, L. Zamai, S. Miscia, and G. Zauli Ionizing radiation sensitizes erythroleukemic cells but not normal erythroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity by selective up-regulation of TRAIL-R1 Blood, May 1, 2001; 97(9): 2596 - 2603. [Abstract] [Full Text] [PDF]
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S. Lacour, A. Hammann, A. Wotawa, L. Corcos, E. Solary, and M.-T. Dimanche-Boitrel Anticancer Agents Sensitize Tumor Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Caspase-8 Activation and Apoptosis Cancer Res., February 1, 2001; 61(4): 1645 - 1651. [Abstract] [Full Text]
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R. Nimmanapalli, M. Porosnicu, D. Nguyen, E. Worthington, E. O’Bryan, C. Perkins, and K. Bhalla Cotreatment with STI-571 Enhances Tumor Necrosis Factor {{alpha}}-related Apoptosis-inducing Ligand (TRAIL or Apo-2L)- induced Apoptosis of Bcr-Abl-positive Human Acute Leukemia Cells Clin. Cancer Res., February 1, 2001; 7(2): 350 - 357. [Abstract] [Full Text]
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R. Nimmanapalli, C. L. Perkins, M. Orlando, E. O’Bryan, D. Nguyen, and K. N. Bhalla Pretreatment with Paclitaxel Enhances Apo-2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis of Prostate Cancer Cells by Inducing Death Receptors 4 and 5 Protein Levels Cancer Res., January 1, 2001; 61(2): 759 - 763. [Abstract] [Full Text]
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J. Wen, N. Ramadevi, D. Nguyen, C. Perkins, E. Worthington, and K. Bhalla Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells Blood, December 1, 2000; 96(12): 3900 - 3906. [Abstract] [Full Text] [PDF]
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W. D. Thomas, X. D. Zhang, A. V. Franco, T. Nguyen, and P. Hersey TNF-Related Apoptosis-Inducing Ligand-Induced Apoptosis of Melanoma Is Associated with Changes in Mitochondrial Membrane Potential and Perinuclear Clustering of Mitochondria J. Immunol., November 15, 2000; 165(10): 5612 - 5620. [Abstract] [Full Text] [PDF]
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N. Özören, K. Kim, T. F. Burns, D. T. Dicker, A. D. Moscioni, and W. S. El-Deiry The Caspase 9 Inhibitor Z-LEHD-FMK Protects Human Liver Cells while Permitting Death of Cancer Cells Exposed to Tumor Necrosis Factor-related Apoptosis-inducing Ligand Cancer Res., November 1, 2000; 60(22): 6259 - 6265. [Abstract] [Full Text]
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J. M. Routes, S. Ryan, A. Clase, T. Miura, A. Kuhl, T. A. Potter, and J. L. Cook Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL) J. Immunol., October 15, 2000; 165(8): 4522 - 4527. [Abstract] [Full Text] [PDF]
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M. Leverkus, H. Walczak, A. McLellan, H.-W. Fries, G. Terbeck, E.-B. Brocker, and E. Kampgen Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand-mediated apoptosis Blood, October 1, 2000; 96(7): 2628 - 2631. [Abstract] [Full Text] [PDF]
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C. S. Seitz, H. Deng, K. Hinata, Q. Lin, and P. A. Khavari Nuclear Factor {{kappa}}B Subunits Induce Epithelial Cell Growth Arrest Cancer Res., August 1, 2000; 60(15): 4085 - 4092. [Abstract] [Full Text]
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N. Mitsiades, V. Poulaki, S. Tseleni-Balafouta, D. A. Koutras, and I. Stamenkovic Thyroid Carcinoma Cells Are Resistant to FAS-mediated Apoptosis But Sensitive to Tumor Necrosis Factor-related Apoptosis-inducing Ligand Cancer Res., August 1, 2000; 60(15): 4122 - 4129. [Abstract] [Full Text]
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S. Hopkins-Donaldson, J.-L. Bodmer, K. B. Bourloud, C. B. Brognara, J. Tschopp, and N. Gross Loss of Caspase-8 Expression in Highly Malignant Human Neuroblastoma Cells Correlates with Resistance to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis Cancer Res., August 1, 2000; 60(16): 4315 - 4319. [Abstract] [Full Text]
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S. Fulda, E. Meyer, and K.-M. Debatin Metabolic Inhibitors Sensitize for CD95 (APO-1/Fas)-induced Apoptosis by Down-Regulating Fas-associated Death Domain-like Interleukin 1-Converting Enzyme Inhibitory Protein Expression Cancer Res., July 1, 2000; 60(14): 3947 - 3956. [Abstract] [Full Text]
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L. Zamai, P. Secchiero, S. Pierpaoli, A. Bassini, S. Papa, E. S. Alnemri, L. Guidotti, M. Vitale, and G. Zauli TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis Blood, June 15, 2000; 95(12): 3716 - 3724. [Abstract] [Full Text] [PDF]
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X. D. Zhang, A. V. Franco, T. Nguyen, C. P. Gray, and P. Hersey Differential Localization and Regulation of Death and Decoy Receptors for TNF-Related Apoptosis-Inducing Ligand (TRAIL) in Human Melanoma Cells J. Immunol., April 15, 2000; 164(8): 3961 - 3970. [Abstract] [Full Text] [PDF]
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K. Kim, M. J. Fisher, S.-Q. Xu, and W. S. El-Deiry Molecular Determinants of Response to TRAIL in Killing of Normal and Cancer Cells Clin. Cancer Res., February 1, 2000; 6(2): 335 - 346. [Abstract] [Full Text]
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S. H. Lee, M. S. Shin, H. S. Kim, H. K. Lee, W. S. Park, S. Y. Kim, J. H. Lee, S. Y. Han, J. Y. Park, R. R. Oh, et al. Alterations of the DR5/TRAIL Receptor 2 Gene in Non-Small Cell Lung Cancers Cancer Res., November 1, 1999; 59(22): 5683 - 5686. [Abstract] [Full Text] [PDF]
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D. J. Panka, T. Mano, T. Suhara, K. Walsh, and J. W. Mier Phosphatidylinositol 3-Kinase/Akt Activity Regulates c-FLIP Expression in Tumor Cells J. Biol. Chem., March 2, 2001; 276(10): 6893 - 6896. [Abstract] [Full Text] [PDF]
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D. Bernard, B. Quatannens, B. Vandenbunder, and C. Abbadie Rel/NF-kappa B Transcription Factors Protect against Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis by Up-regulating the TRAIL Decoy Receptor DcR1 J. Biol. Chem., July 13, 2001; 276(29): 27322 - 27328. [Abstract] [Full Text] [PDF]
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E. R. McDonald III, P. C. Chui, P. F. Martelli, D. T. Dicker, and W. S. El-Deiry Death Domain Mutagenesis of KILLER/DR5 Reveals Residues Critical for Apoptotic Signaling J. Biol. Chem., April 27, 2001; 276(18): 14939 - 14945. [Abstract] [Full Text] [PDF]
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T. F. Burns and W. S. El-Deiry Identification of Inhibitors of TRAIL-induced Death (ITIDs) in the TRAIL-sensitive Colon Carcinoma Cell Line SW480 Using a Genetic Approach J. Biol. Chem., October 5, 2001; 276(41): 37879 - 37886. [Abstract] [Full Text] [PDF]
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 A. K. Simon, O. Williams, J. Mongkolsapaya, B. Jin, X. N. Xu, H. Walczak, and G. R. Screaton Tumor necrosis factor-related apoptosis-inducing ligand in T cell development: Sensitivity of human thymocytes PNAS, April 24, 2001; 98(9): 5158 - 5163. [Abstract] [Full Text] [PDF]
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